Omega 3 fatty acids and the brain : review of studies in depression

The brain is a lipid-rich organ containing mostly complex polar  phospholipids, sphingolipids, gangliosides and cholesterol. These lipids are involved in the structure and function of cell membranes in the brain. The glycerophospholipids in the brain contain a high proportion of  polyunsaturated fatty acids (PUFA) derived from the essential fatty acids, linoleic acid and alpha-linolenic acid. The main PUFA in the brain are docosahexaenoic acid (DHA, all cis 4,7,10,13,16,19-22:6) derived from the omega 3 fatty acid, alpha-linolenic acid, and arachidonic acid (AA, all cis 5,8,11,14-20:4) and docosatetraenoic acid (all cis 7,10,13,16-22:4), both derived from the omega 6 fatty acid, linoleic acid. Experimental studies in animals have shown that diets lacking omega 3 PUFA lead to substantial disturbances in neural function, which in most circumstances can be restored by the inclusion of omega 3 PUFA in the diet. In the past 10 years there has been an emerging interest in treating neuropsychological  disorders (depression and schizophrenia) with omega 3 PUFA. This paper discusses the clinical studies conducted in the area of depression and omega 3 PUFA and the possible mechanisms of action of these PUFA. It is clear from the literature that DHA is involved in a variety of processes in neural cells and that its role is far more complex than simply influencing cell membrane properties.

Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids

Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans.
Materials and methods Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic–euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR.
Results Lipid infusion resulted in a ∼2.7-fold increase in plasma NEFA levels and a 31±6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a ∼1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to ∼53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to ∼61, 77 and ∼52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05).
Conclusions/interpretation Acute elevation of plasma NEFA levels, leading to muscular fat accumulation and insulin resistance, downregulates PPARGC1A, PPARGC1B and PPARA expression, suggesting that the decrease in PPARGC1 expression observed in the (pre)diabetic state may be the result, rather than the cause of lipid-induced insulin resistance.

Effect of diets containing n-3 fatty acids on muscle long-chain n-3 fatty acid content in lambs fed low- and medium-quality roughage diets

In two experiments, each with 32 crossbred ([Merino x Border Leicester] x Poll Dorset) wether lambs (26 to 33 kg weight range), animals were randomly assigned to one of four treatments. A mixture of lucerne chaff:oaten chaff was used as a basal diet, offered in different ratios. Animals were allowed to consume on a free-access basis in Exp. 1 or 90% of ad libitum intake in Exp. 2 in order to provide a low- (6.5 MJ ME/d) and medium- (9.5 MJ ME/d) quality basal diet, respectively. Isoenergetic amounts of lipid supplements, fish meal (80 g DM), canola meal (84 g DM), and soy meal (75 g DM) were tested in Exp. 1. In Exp. 2, fish meal (9% DM), unprotected rapeseed (7% DM), and protected canola seed (6% DM) were fed as supplements. At the end of 53-d (Exp. 1) or 46-d (Exp. 2) experimental periods, lambs were slaughtered at a commercial abattoir and at 24 h postmortem longissimus thoracis (LT) muscle was collected for the analysis of fatty acid (FA) composition of structural phospholipid and storage triglyceride fractions. Fish meal diet increased LT muscle long-chain n-3 FA content by 27% (P < 0.02) in Exp. I and 30% (P < 0.001) in Exp. 2 compared with lambs fed the basal diet, but fish meal decreased (P < 0.01) the n-6 FA content only in Exp. 1. Soy meal and protected canola seed diets increased (P < 0.01) LT muscle n-6 FA content but did not affect long-chain n-3 FA content. Longissimus thoracis muscle long-chain n-3 FA were mainly deposited in structural phospholipid, rather than in storage triglyceride. In both Exp. 1 and Exp. 2, the ratio of n-6:n-3 FA in LT muscle was lowest (P < 0.01) in lambs fed fish meal supplement compared with all other treatments. Protected canola seed diet increased the ratio of n-6:n-3 FA (P < 0.01) and PUFA:saturated fatty acid (P < 0.03) content from those animals fed the basal, fish meal, and unprotected rapeseed diets in Exp. 2. This was due to an increase in muscle n-6 FA content, mainly linoleic acid, of both phospholipid (P < 0.001) and triglyceride (P < 0.01) fractions and not to an increase in muscle n3 FA content. The results indicate that by feeding fish meal supplement, the essential n-3 FA can be increased while lowering the ratio of n-6:n-3 content in lamb meat to an extent that could affect nutritional value, attractiveness, and the economic value of meat.

Dietary manipulation of muscle long-chain omega-3 and omega-6 fatty acids and sensory properties of lamb meat

The effects of dietary manipulation of muscle long-chain omega-3 fatty acids (FA) on sensory properties of cooked meat in second cross ([Merino×Border Leicester]×Poll Dorset) wether lambs were evaluated. Lambs fed dietary supplements of fish meal (FM, Exp. 1) and fish oil (FO, Exp. 2) showed moderately (P<0.01) and markedly (P<0.001) increased muscle long-chain omega-3 FA content compared with those fed the basal diet of lucerne chaff and oat chaff. Protected canola seed (PCS, Exp. 1) significantly (P<0.001) increased omega-6 FA content of the longissimus muscle. In each of the 2 experiments (1 and 2), after being fed experimental diets for 6 weeks lambs were slaughtered at a commercial abattoir. At 24 h post-mortem (PM) the semitendinosus and biceps femoris muscles were removed from animals and stored at −20°C until evaluation of sensory properties using experienced panel members. The muscle samples were stored for 3 (Exp. 1) and 12 (Exp. 2) months then removed, thawed and cooked for sensory evaluation. The meat samples were cooked under standardized conditions in a convection microwave at 180°C (20–25 min) to an internal temperature of 75°C. Cooked samples were tested for flavour, aroma, juiciness and overall palatability. The significant increase in muscle long-chain omega-3 with FM (Exp. 1 and 2) and FO (Exp. 2) or omega-6 FA with PCS (Exp. 1) were not detrimental to sensory panel evaluations of flavour or aroma of cooked meat when compared with the basal diet. However, meat from FM (Exp. 1) had lower juiciness and FO (Exp. 2) had lower overall palatability. Protected sunflower meal protein with FO (Exp. 2) significantly lowered ratings for flavour, juiciness and overall palatability. Lamb meat with increased levels of long-chain omega-3 FA can be produced without altering the sensory quality (flavour or aroma) of the cooked meat.

Dietary intakes and food sources of Omega-6 and Omega-3 polyunsaturated fatty acids.

Both n−6 and n−3 polyunsaturated fatty acids (PUFA) are recognized as essential nutrients in the human diet, yet reliable data on population intakes are limited. The aim of the present study was to ascertain the dietary intakes and food sources of individual n−6 and n−3 PUFA in the Australian population. An existing database with fatty acid composition data on 1690 foods was updated with newly validated data on 150 foods to estimate the fatty acid content of foods recorded as eaten by 10,851 adults in the 1995 Australian National Nutrition Survey. Average daily intakes of linoleic (LA), arachidonic (AA), α-linolenic (LNA), eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexaenoic (DHA) acids were 10.8, 0.052, 1.17, 0.056, 0.026, and 0.106 g, respectively, with longchain (LC) n−3 PUFA (addition of FPA, DPA, and DHA) totaling 0.189 g; median intakes were considerably lower (9.0 g LA, 0.024 g AA, 0.95 g LNA, 0.008 g EPA, 0.006 g DPA, 0.015 g DHA, and 0.029 g LC n−3 PUFA). Fats and oils, meat and poultry, cereal-based products and cereals, vegetables, and nuts and seeds were important sources of n−6 PUFA, while cereal-based products, fats and oils, meat and poultry, cereals, milk products, and vegetable products were sources of LNA. As expected, seafood was the main source of LC n−3 PUFA, contributing 71%, while meat and eggs contributed 20 and 6%, respectively. The results indicate that the majority of Australians are failing to meet intake recommendations for LC n−3 PUFA (>0.2 g per day) and emphasize the need for strategies, to increase the availability and consumption of n−3-containing foods.

Bread enriched with microencapsulated tuna oil increases plasma docosahexaenoic acid and total omega-3 fatty acids in humans

The aim of this study was to determine the acute and chronic effects of low doses of long chain (LC) n-3 polyunsaturated fatty acids (PUFA) (<100 mg per day) on plasma LC n-3 PUFA levels using a novel delivery form; bread containing microencapsulated tuna oil (MTO). Six omnivores (three men and three women) participated in the acute study, which involved ingesting a prototype MTO bread containing approximately 80 mg of LC n-3 PUFA/four slices. Plasma triacylglycerol fatty acid compositions were measured after an overnight fast and postprandially at 2 and 4 h. In the chronic study, 10 vegetarian subjects (nine men and one woman) consumed MTO bread at six to eight slices/day (comprising 60 mg of LC n-3 PUFA) as the only dietary source of these PUFA for three weeks. Fasting plasma total and phospholipid fatty acid compositions were measured at baseline and endpoint. In the acute study, the proportions of 22:6 n-3 and total n-3 PUFA in plasma triacylglycerol were significantly increased (P < 0.05). In the chronic study, the proportions of 20:5 n-3, 22:5 n‐3, 22:6 n-3, total n-3 PUFA in plasma, and 22:6 n-3 and total n-3 PUFA in plasma phospholipid fractions were significantly increased (P < 0.05) at the endpoint compared with the baseline. This study showed that a low dose of LC n-3 PUFA, consumed as MTO-enriched bread, was bioavailable, as measured by an increase in LC n-3 PUFA levels in the plasma of human subjects.

Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression

Polyunsaturated fatty acids (PUFA) are essential structural components of the central nervous system. Their role in controlling learning and memory has been well documented. A nutrigenomic approach with high-density microarrays was used to reveal brain gene-expression changes in response to different PUFA-enriched diets in rats. In aged rats fed throughout life with PUFA-enriched diets, genes with altered expressions included transthyretin, α-synuclein, and calmodulins, which play important roles in synaptic  plasticity and learning. The effect of perinatal omega-3 PUFA supply on gene expression later in life also was studied. Several genes showed similar changes in expression in rats fed omega-3-deficient diets in the perinatal period, regardless of whether they or their mothers were fed omega-3 PUFA-sufficient diets after giving birth. In this experiment, among the down-regulated genes were a kainate glutamate receptor and a DEAD-box polypeptide. Among the up-regulated genes were a chemokine-like factor, a tumor necrosis factor receptor, and cytochrome c. The possible involvement of the genes with altered expression attributable to different diets in different brain regions in young and aged rats and the possible mode of regulatory action of PUFA also are discussed. We conclude that PUFA-enriched diets lead to significant changes in expression of several genes in the central nervous tissue, and these effects appear to be mainly independent of their effects on membrane composition. The direct effects of PUFA on transcriptional modulators, the downstream developmentally and tissue-specifically activated elements might be one of the clues to understanding the beneficial effects of the omega-3 PUFA on the nervous system.

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

The role of omega-3 fatty acids in mood disorders

Research has established that docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid (PUFA), plays a fundamental role in brain structure and function. Epidemiological and cross-sectional studies have also identified a role for long-chain omega-3 PUFA, which includes DHA, eicosapentaenoic acid, and docosapentaenoic acid, in the etiology of depression. In the past ten years, there have been 12 intervention studies conducted using various preparations of longchain omega-3 PUFA in unipolar and bipolar depression. The majority of these studies administered long-chain omega-3 PUFA as an adjunct therapy. The studies have been conducted over 4 to 16 weeks of intervention and have often included small cohorts. In four out of the seven studies conducted in depressed individuals and in two out of the five studies in bipolar patients, individuals have reported a positive outcome following supplementation with ethyl-eicosapentaenoic acid or fish oil containing long-chain omega-3 PUFA. In the three trials that researched the influence of DHA-rich preparations, no significant effects were reported. The mechanisms that have been invoked to account for the benefits of long-chain omega-3 PUFA in depression include reductions in prostaglandins derived from arachidonic acid, which lead to decreased brain-derived neurotrophic factor levels and/or alterations in blood flow to the brain.